Improvement of thrombosis management in patients with cancer: a practical consensus document of recommendations for cancer-associated thrombosis patients' healthcare in Spain.

Cancer patients are at risk of venous thromboembolism (VTE), its recurrence, but also at risk of bleeding while anticoagulated. In addition, cancer therapies have been associated to increased VTE risk. Guidelines for VTE treatment in cancer patients recommend low molecular weight heparins (LMWH) or direct oral anticoagulants (DOAC) for the initial treatment, DOAC for VTE short-term treatment, and LMWH or DOAC for VTE long-term treatment. This consensus article arises from a collaboration between different Spanish experts on cancer-associated thrombosis. It aims to reach an agreement on a practical document of recommendations for action allowing the healthcare homogenization of cancer-associated thrombosis (CAT) patients in Spain considering not only what is known about VTE management in cancer patients but also what is done in Spanish hospitals in the clinical practice. The text summarizes the current knowledge and available evidence on the subject in Spain and provides a series of practical recommendations for CAT management and treatment algorithms to help clinicians to manage CAT over time.

Use of direct oral anticoagulants and low molecular weight heparin in venous thromboembolism associated with cancer: real-world evidence in Argentina.

BACKGROUND: Venous thromboembolism (VTE) and major bleeding (MB) are common in cancer patients. Reduced-doses of antithrombotics as secondary prophylaxis have limited data. This work aims to describe and to compare treatments and outcomes for cancer-associated VTE. RESEARCH DESIGN AND METHODS: Retrospective study. Adults with cancer-associated VTE were included. After 3-6 months of full-doses of anticoagulants, three strategies were considered: A) lowering the doses; B) maintaining full-doses; C) stopping treatment. The strategy and medication used were shown in a descriptive analysis and the rate of bleeding and VTE-recurrence between those in a comparative analysis. RESULTS: A total of 420 patients were included, 56.2% received DOACs, 43.8% enoxaparin. Strategy was defined in 257 patients: A (50.2%), B (46.3%), and C (3.5%). Forty-one (9.8%) had VTE-recurrence and 15 (3.6%) had MB or clinically relevant non-major bleeding (CRNMB).According to strategy, recurrent-VTE was 8.5% (A), 4.2% (B), and 11.1 (C) (p = 0.22), MB or CRNMB was 0.8% (A), 1.7% (B), and 0% (C) (p = 0.64). CONCLUSIONS: DOACs and strategy A were the most frequently used agent and strategy, respectively. There were no differences between medications or strategies used. The results must be interpreted with caution, and it is a retrospective single-center study, probably with information and selection bias.

Current state of non-hematologic cancer-associated thrombosis at a tertiary care hospital in India

Abstract Introduction Cancer-associated thrombosis is a leading cause of morbidity and mortality in malignancy patients. Prophylactic anticoagulation is under-utilized and the cost of low-molecular-weight heparin (LMWH) and direct oral anticoagulants is a major barrier in developing countries. Material and methods A retrospective analysis was performed of all cancer-associated thrombosis patients attending the thrombosis clinic at a tertiary-level referral hospital based in North India between 2011 and 2015. Patient demographics and disease-related parameters were collected and analyzed. Results A total of 771 patients attended the thrombosis clinic during study period, of which 64 cases were malignancy-associated. Of these, 56% of the patients were female and 20% were bedridden. The median age was 48.5 years, adenocarcinoma (48%) being the most common histological subtype. Gynecological malignancies (30%) were the most common malignancies, followed by genitourinary (11%) malignancies. Most of the cases occurred during first year of diagnosis (51%), and only 14% occurred after 3 years. Most of the patients were on combined treatment. Almost 40% of the patients developed thrombosis within 30 days of surgical treatment. Lower limb thrombosis was the most commonly seen type (56%), while abdominal and pulmonary thrombosis were both seen in 5%. Patients were managed with LMWH and vitamin K antagonists (84.3%) and only 6.25% with LMWH alone. Direct oral anticoagulants were not commonly used during the study period. Discussion At the hospital studied, most of the cases occurred early in the disease course. Postoperative prophylaxis could have contributed towards reducing thrombosis in the peri-operative period. Early suspicion and prompt treatment can improve quality of life in such patients.

Current state of non-hematologic cancer-associated thrombosis at a tertiary care hospital in India.

INTRODUCTION: Cancer-associated thrombosis is a leading cause of morbidity and mortality in malignancy patients. Prophylactic anticoagulation is under-utilized and the cost of low-molecular-weight heparin (LMWH) and direct oral anticoagulants is a major barrier in developing countries. MATERIAL AND METHODS: A retrospective analysis was performed of all cancer-associated thrombosis patients attending the thrombosis clinic at a tertiary-level referral hospital based in North India between 2011 and 2015. Patient demographics and disease-related parameters were collected and analyzed. RESULTS: A total of 771 patients attended the thrombosis clinic during study period, of which 64 cases were malignancy-associated. Of these, 56% of the patients were female and 20% were bedridden. The median age was 48.5 years, adenocarcinoma (48%) being the most common histological subtype. Gynecological malignancies (30%) were the most common malignancies, followed by genitourinary (11%) malignancies. Most of the cases occurred during first year of diagnosis (51%), and only 14% occurred after 3 years. Most of the patients were on combined treatment. Almost 40% of the patients developed thrombosis within 30 days of surgical treatment. Lower limb thrombosis was the most commonly seen type (56%), while abdominal and pulmonary thrombosis were both seen in 5%. Patients were managed with LMWH and vitamin K antagonists (84.3%) and only 6.25% with LMWH alone. Direct oral anticoagulants were not commonly used during the study period. DISCUSSION: At the hospital studied, most of the cases occurred early in the disease course. Postoperative prophylaxis could have contributed towards reducing thrombosis in the peri-operative period. Early suspicion and prompt treatment can improve quality of life in such patients.

Platelets and extracellular vesicles and their cross talk with cancer.

Platelets play significant and varied roles in cancer progression, as detailed throughout this review series, via direct interactions with cancer cells and by long-range indirect interactions mediated by platelet releasates. Microvesicles (MVs; also referred to as microparticles) released from activated platelets have emerged as major contributors to the platelet-cancer nexus. Interactions of platelet-derived MVs (PMVs) with cancer cells can promote disease progression through multiple mechanisms, but PMVs also harbor antitumor functions. This complex relationship derives from PMVs' binding to both cancer cells and nontransformed cells in the tumor microenvironment and transferring platelet-derived contents to the target cell, each of which can have stimulatory or modulatory effects. MVs are extracellular vesicles of heterogeneous size, ranging from 100 nm to 1 µm in diameter, shed by living cells during the outward budding of the plasma membrane, entrapping local cytosolic contents in an apparently stochastic manner. Hence, PMVs are encapsulated by a lipid bilayer harboring surface proteins and lipids mirroring the platelet exterior, with internal components including platelet-derived mature messenger RNAs, pre-mRNAs, microRNAs, and other noncoding RNAs, proteins, second messengers, and mitochondria. Each of these elements engages in established and putative PMV functions in cancer. In addition, PMVs contribute to cancer comorbidities because of their roles in coagulation and thrombosis and via interactions with inflammatory cells. However, separating the effects of PMVs from those of platelets in cancer contexts continues to be a major hurdle. This review summarizes our emerging understanding of the complex roles of PMVs in the development and progression of cancer and cancer comorbidities.

Rationale, design and methodology of TESEO study: a registry of thrombosis and neoplasia of SEOM (Spanish Society of Medical Oncology).

BACKGROUND AND RATIONALE: Thromboembolic complications are a serious, preventable and common event in cancer patients that contributes to increasing morbidity and mortality. Despite increasing knowledge on cancer-associated thrombosis (CAT), there are still several aspects of diagnosis, clinical management, treatment and prognosis with uncertainties that are under-represented in randomized clinical trials. For this reason, the Spanish Society of Medical Oncology (SEOM) launched in June 2018 a registry of CAT. METHODS/DESIGN: TESEO is an ongoing prospective, non-interventional, multicentric study in consecutive cancer patients with newly diagnosed of thromboembolic event (TEE). Eligibility criteria include being > 18 years with a histologically confirmed diagnosis of cancer and a symptomatic or incidental TEE confirmed with an imaging technique in the previous month or any time after the cancer diagnosis and signing of informed consent. The study consists of two types of integrated but independent prospective registries. Regular CAT sub-registry includes information on patient's cancer´s characteristics, anticoagulant treatment provided and outcome data. Special CAT sub-registry includes variables related to special situations of CAT that comprise patients with severe kidney failure, thrombocytopenia, high risk of bleeding related to the cancer or with coexistence of bleeding and patients who receive new treatments such a targeted therapy, antiangiogenics agents and immunotherapy. The registry considers the status of the cancer and the time to assess how the prognosis is changed based on when the thrombus occurs. Some outcomes such as rethrombosis, major bleeding, tumor progression and survival will be valued in various time intervals including 1, 3, 6 and 12 months after the even in the first year; and then every 6 months until the patient's death. RESULTS: After 18 months and with 35 centers and researchers, the registry has 1128 patients. CONCLUSION: TESEO registry will provide clinical real-world evidence for prevention, treatment and complications of CAT in different scenarios that are under-represented in randomized clinical trials.

Deciphering the Role of the Coagulation Cascade and Autophagy in Cancer-Related Thrombosis and Metastasis.

Thrombotic complications are the second leading cause of death among oncology patients worldwide. Enhanced thrombogenesis has multiple origins and may result from a deregulation of megakaryocyte platelet production in the bone marrow, the synthesis of coagulation factors in the liver, and coagulation factor signaling upon cancer and the tumor microenvironment (TME). While a hypercoagulable state has been attributed to factors such as thrombocytosis, enhanced platelet aggregation and Tissue Factor (TF) expression on cancer cells, further reports have suggested that coagulation factors can enhance metastasis through increased endothelial-cancer cell adhesion and enhanced endothelial cell activation. Autophagy is highly associated with cancer survival as a double-edged sword, as can both inhibit and promote cancer progression. In this review, we shall dissect the crosstalk between the coagulation cascade and autophagic pathway and its possible role in metastasis and cancer-associated thrombosis formation. The signaling of the coagulation cascade through the autophagic pathway within the hematopoietic stem cells, the endothelial cell and the cancer cell are discussed. Relevant to the coagulation cascade, we also examine the role of autophagy-related pathways in cancer treatment. In this review, we aim to bring to light possible new areas of cancer investigation and elucidate strategies for future therapeutic intervention.

Incidence of venous thromboembolism in patients with colorectal cancer according to oncogenic status.

BACKGROUND: There are conflicting data regarding the role of KRAS mutation on the risk of venous thromboembolism (VTE) in colorectal cancer (CRC) patients. Moreover, the role of other biomarkers such as NRAS or BRAF has not been studied. PURPOSE: To analyze the incidence of VTE in a cohort of patients with CRC based on KRAS, NRAS, and BRAF status. METHODS: We performed a retrospective review of patients with unresectable locally advanced and metastatic CRC (mCRC) and known KRAS/NRAS/BRAF status, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain). The primary outcome was VTE defined as any venous thromboembolic event that occurred either 6 months before or at any time after the diagnosis of CRC. The biomarker status (KRAS, NRAS, and BRAF) and other predictors of thrombosis were collected. RESULTS: One hundred and ninety-four patients were identified and included in the analysis. Forty-one patients (21.1%) experienced VTE. The incidence was 19.1% in RAS-mutated patients, 28.6% in BRAF-mutated patients and 21% in triple wild-type patients (p = NS). In multivariate analysis, ECOG ≥ 2 was the only independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). CONCLUSIONS: In our study, biomarkers have not been associated with an increased risk of VTE in CRC patients. A high incidence of VTE in BRAF-mutated patients has been observed and should be explored in further studies.

FOTROCAN Delphi consensus statement regarding the prevention and treatment of cancer-associated thrombosis in areas of uncertainty and low quality of evidence.

INTRODUCTION: Decision-making in cancer-related venous thromboembolism (VTE) is often founded on scant lines of evidence and weak recommendations. The aim of this work is to evaluate the percentage of agreement surrounding a series of statements about complex, clinically relevant, and highly uncertain aspects to formulate explicit action guidelines. MATERIALS AND METHODS: Opinions were based on a structured questionnaire with appropriate scores and were agreed upon using a Delphi method. Questions were selected based on a list of recommendations with low evidence from the Spanish Society of Oncology Clinical Guideline for Thrombosis. The questionnaire was completed in two iterations by a multidisciplinary panel of experts in thrombosis. RESULTS: Of the 123 statements analyzed, the panel concurred on 22 (17%) and another 81 (65%) were agreed on by qualified majority, including important aspects of long-term and prolonged anticoagulation, major bleeding and rethrombosis management, treatment in special situations, catheter-related thrombosis and thromboprophylaxis. Among them, the panelists agreed the incidental events should be equated to symptomatic ones, long-term and extended use of full-dose low-molecular weight heparin, and concluded that the Khorana score is not sensitive enough to uphold an effective thromboprophylaxis strategy. CONCLUSION: Though the level of consensus varied depending on the scenario presented, overall, the iterative process achieved broad agreement as to the general treatment principles of cancer-associated VTE. Clinical validation of these statements in genuine practice conditions would be useful.